Molecular and cellular mechanisms of cardiotoxicity.

Abstract

Cardiotoxicity resulting from detrimental environmental insults has been recognized for a long time. However, extensive studies of the mechanisms involved had not been undertaken until recent years. Advances in molecular biology provide powerful tools and make such studies possible. We are gathering information about cellular events, signaling pathways, and molecular mechanisms of myocardial toxicologic responses to environmental toxicants and pollutants. Severe acute toxic insults cause cardiac cell death instantly. In the early response to mild environmental stimuli, biochemical changes such as alterations in calcium homeostasis occur. These may lead to cardiac arrhythmia, which most often is reversible. Prolonged stimuli activate transcription factors such as activator protein-1 through elevation of intracellular calcium and the subsequent activation of calcineurin. Upregulation by activated transcription factors of hypertrophic genes results in heart hypertrophy, which is a short-term adaptive response to detrimental factors. However, further development of hypertrophy will lead to severe and irreversible cardiomyopathy, and eventually heart failure. From cardiac hypertrophy to heart failure, myocardial cells undergo extensive biochemical and molecular changes. Cardiac hypertrophy causes tissue hypoperfusion, which activates compensatory mechanisms such as production of angiotensin II and norepinephrine. Both further stimulate cardiac hypertrophy and, importantly, activate counterregulatory mechanisms including overexpression of atrial natriuretic peptide and b-type natriuretic peptide, and production of cytokines such as tumor necrosis factor-alpha. This counterregulation leads to myocardial remodeling as well as cell death through apoptosis and necrosis. Cell death through activation of mitochondrial factors and other pathways constitutes an important cellular mechanism of heart failure. Our current knowledge of cardiotoxicity is limited. Further extensive studies are warranted for a comprehensive understanding of this field.

Roles of insulin-like growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation

“…Most of the evidence indicates that the stimulation of ANG II in the heart is associated with an increased rate of myocardial apoptosis (9,16). Although the mechanism of apoptosis enhanced by ANG II is still controversial due to a variety of possible pathways, the calciumcalcineurin pathway has been regarded as an important one for ANG II-induced apoptosis in cardiac cells (14,19,21). ANG II has been shown to activate calcineurin through G␣ q /PLC signaling transduction.…”

Efek Asam Alfa Lipoat pada Kadar MDA dan Histologi Ginjal Tikus Wistar Diabetes Melitus Tipe1

“…ALA juga menunjukkan hasil yang lebih tinggi dibandingkan dengan bermanfaat sebagai antiinflamasi dengan menghambat kelompok lainnya. Hal ini menujukkan bahwa stres aktivasi faktor nuklear κB (NF-κB) (14). Pada kelompok oksidatif pada kelompok DA80 lebih besar dibandingkan DA500, jaringan stroma yang rusak lebih parah dan dengan kelompok perlakuan yang lain.…”

Oxidative Stress and Novel Antioxidant Approaches to Reduce Diabetic Complications

“…Furthermore, hyperglycaemia-mediated oxidative stress has been shown to cause abnormal gene expression, altered signal transduction, and the activation of pathways leading to myocyte apoptosis (Cai & Kang 2001). Myocyte death causes a loss of contractile units, compensatory hypertrophy of myocytes and reparative fibrosis, all characteristics of diabetic cardiomyopathy (Kang 2001). In a study by Frustaci et al (2000), increased levels of nitrotyrosine were associated with apoptosis and necrosis of cardiac cells including myocytes, endothelial cells and fibroblasts in patients with diabetes, as well as in STZ-induced diabetic mice (Cai et al 2005).…”